Dihydrocodeine is a widely used semisynthetic narcotic analgesic possessing also useful antitussive properties. It is also an important intermediate for the synthesis of other opioid analgesics, e.g. hydrocodone.
Dihydrocodeine has been prepared by hydrogenation of neopine (J. Chem Soc. (1926), 903). However, since neopine is one of the least available morphine alkaloids this method has little practical value.
Another method of dihydrocodeine preparation is described in U.S. Pat. Nos. 3,830,819 and 3,853,883 as hydrogenation of hydrocodone. Hydrocodone itself is usually produced from codeine or thebaine by multi-step synthetic transformations. As compared to the synthesis from codeine, which is discussed below, this adds additional steps to the process, leading to dihydrocodeine production that is not cost-effective.
Hydrogenation of codeine in the presence of palladium catalysts is a straightforward method of dihydrocodeine preparation (Ann. (1923), 433, 269, J. Org. Chem. (1950), 15, 1103; Synth. Commun. (2000), 30, 3195). Usually hydrogenation requires large amounts of organic solvents, leading to increased health risk for the manufacturing personnel, and also posing environmental hazard. These disadvantages of organic solvents may be eliminated by using water as a safe, so-called “green” solvent. However, in aqueous solutions (J. Org. Chem. (1950), 15, 1105), hydrogenation is complicated by uncontrollable side reactions, because metal catalysts used for the hydrogenation induce isomerization of codeine to hydrocodone and also promote cleavage of the 4,5-epoxymorphinane ring of the molecule to form dihydrothebainone. Removal of these impurities from dihydrocodeine to the levels acceptable for the pharmaceutical use is a very tedious process, resulting in substantial yield loss.
In view of above, there is a need for an efficient, economical, safe and environmentally friendly process for the production of dihydrocodeine.